Engineering Models of Neuroimmune Sensitization to Elucidate Mechanisms of Pain Resolution

Chronic pain affects up to 20% of all people in the United States and involves changes in peripheral tissues (i.e. skin, muscle), the spinal cord, and the brain. Current models of chronic pain fail to replicate the complexity of the body and thus fail to develop new treatments that translate to patients. This project seeks to engineer new bench top models that accurately mimic the features of chronic pain in the periphery; and increase understanding of how chronic pain develops, is maintained, and can be resolved. This research will also explore how the immune system can help resolve chronic pain. Project implementation includes integrated education/outreach activities designed to increase interest in science among diverse populations and across students of multiple ages. The team will incorporate primary neuronal culture into the Tissue Engineering curriculum at the University of Nebraska-Lincoln to lower the barrier to entry in the neural engineering field. Further, the team will develop and implement fun, interactive lessons and labs to teach middle school students and Osher Lifelong Learning Institute members (serving people over the age of 50) about biomedical engineering and chronic pain. The goal of this research is to create in vitro models that replicate the physiological complexity in peripheral tissue present during chronic pain to increase mechanistic understanding and identify novel targets to treat peripheral pain. The most common peripheral feature of pain is a lowered stimulation threshold of painful neurons termed nociceptor hypersensitivity. The high rate of translational failure of pain therapeutics in clinical trials that have demonstrated efficacy in animal models motivates the need for more effective tools and mechanistic knowledge. In vitro models of primary sensory neurons and associated cells that accurately mimic the peripheral features of chronic pain hold great promise to understand mechanisms of chronic pain and develop new treatment targets. However, to date, most in vitro models of lowered neuronal thresholds or nociceptor hypersensitivity have limitations. Objective 1 will engineer a physiologically relevant multi-compartment model of nociceptor hypersensitivity and validate its response using noxious stimuli. Objective 2 will establish a neuroimmune-specific model of nociceptor hypersensitization to test anti-inflammatory macrophage mechanisms of resolution by co-culturing macrophages of varying phenotypes in the neurite compartments. In vitro models of peripheral pain features hold great promise to enhance understanding of the mechanisms driving pain and translational efficacy of treatments. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.